Graves' disease is an autoimmune disease that affects the thyroid. It is characterised by an overactive thyroid gland, which results in the production of an excessive amount of thyroid hormone and enlargement of the thyroid gland (goitre). The resulting state of hyperthyroidism may cause a wide range of neuropsychological and physical symptoms. Graves' disease is the most common cause of hyperthyroidism (60-90% of all cases) and usually presents itself during midlife, but also appears in children, adolescents, and the elderly. It affects up to 2% of the female population and is between five and ten times as common in females as in males. Paediatric Graves' disease affects about 6,000 children in the United States (US) and 6,000 in the European Union (EU). Graves' disease is also the most common cause of severe hyperthyroidism, which is accompanied by more clinical signs and symptoms and laboratory abnormalities as compared with milder forms of hyperthyroidism.
There is a strong hereditary component linked to Graves' disease. There are no recent population studies on Graves' disease, however, a few quasi population studies on hyperthyroidism do exist and all estimates for incidence and prevalence of Graves' disease are thus approximate. The incidence of hyperthyroidism varies from 26:100,000 to 93:100,000 and the overall prevalence is estimated to be at 1.3%, with 40% of cases being overt and 60% subclinical.
About 30-50% of people with Graves' disease will also suffer from Graves' opthalmopathy (also known as Graves' orbitopathy or thyroid eye disease) (GO), a protrusion of one or both eyes. Many cases of GO are mild and self-limiting, however 20% of cases have significant/moderate to severe disease, with at least half of these requiring steroids and 3-5% of GO patients have painful, sight-threatening disease with dysthyroid optic neuropathy. The buldging of the eyes may cause severe dryness of the cornea as the eye lids are unable to close at night. Increased pressure on the optic nerve can lead to visual field defects and vision loss. GO may also be associated with pretibial myxedemia.
The symptoms and signs of Graves' disease virtually all result from the direct and indirect effects of hyperthyroidism, with main exceptions being GO, goitre and pretibial myxedema. Symptoms of hyperthyroidism may include insomnia, hand tremor, hyperactivity, hair loss, excessive sweating, heat intolerance and weight loss despite increased appetite. Further signs are most commonly a diffusely enlarged (usually symmetric) non-tender thyroid, lid lag, excessive lacrimation due to GO, arrhythmias of the heart and hypertension. Thyrotoxic patients may experience behavioural and personality changes, such as psychosis, agitation, and depression. In milder hyperthyroidism, patients may experience less overt manifestations, for example anxiety, restlessness, irritability and emotional lability.
There is currently no cure available for Graves' disease and present treatments are therefore directed towards targeting the presenting symptoms. There are three treatment modalities for Graves' disease, oral antithyroid drugs (ATDs), radioactive iodine (RAI) and thyroidectomy. The latter two approaches result in lifetime supplementation of thyroid hormones. Therapy with RAI is the most common treatment in the US, whilst ATDs are the first line treatment in Europe, Japan and most of the rest of the world.
ATD therapy is associated with some rare side-effects and has a remission rate of 50-60%. There is growing recognition that RAI can precipitate or worsen active GO and the number of patients treated with ATDs is the United States is increasing.
Due to the varying success of each treatment option, patients are often subjected to more than one approach if the first attempted treatment does not prove entirely successful. The risk of relapse or subsequent hypothyroidism is substantial and the general efficacy of available treatments for Graves' disease is less than desired.
The development of alternative therapies for Graves' disease has been hampered by a lack of relevant models, in particular animal models, for assessing the potential efficacy of candidate therapies. Known BALB/c mouse models for Graves' disease have not been tested for efficacy with approved drugs for Graves' disease, such as methimazole and methylprednisolone.
There is thus a need for alternative therapies for treating and preventing diseases associated with the production of TSHR autoantibodies, such as Graves' disease. Alternative therapies that are effective at treating Graves' disease and at alleviating or reducing the symptoms of the disease are thus needed. There is also a need for alternative models for assessing the potential efficacy of candidate Graves' disease therapies.